Investigation Drug-drug Interaction Between Dabigatran and Clarithromycin

Condition(s) targeted: Healthy

Intervention: Dabigatran then dabigatran and clarithromycin (Drug); Clarithromycin and dabigatran then dabigatran (Drug)

Phase: Phase 1

Status: Completed

Sponsored by: Centre Hospitalier Universitaire de Saint Etienne

Official(s) and/or principal investigator(s):
Patrick MISMETTI, MD PhD, Principal Investigator, Affiliation: CHU de Saint-Etienne
Xavier DELAVENNE, Pharmacist, Study Chair, Affiliation: CHU de Saint-Etienne

Dabigatran (Pradaxa ®) is a new oral anticoagulant. It is used to prevent venous thromboembolism in orthopedic surgery and has recently demonstrated efficacy and safety at least as good as anticoagulants in the prevention of thromboembolism in atrial fibrillation and the treatment of venous thromboembolism. It is administered with fixed dose and does not require laboratory monitoring because of the low inter and intra individual pharmacokinetic (PK) and pharmacodynamics (PD) of dabigatran. However, the bioavailability of dabigatran is very low (6. 5%) and is controlled by an efflux protein, P-GP. This molecule has a genetic polymorphism. The inhibition of this protein can cause a significant increase in intestinal absorption of dabigatran and expose patients to a risk of bleeding by overdose. Two major drug interactions have been identified : quinidine (cons-indication) and amiodarone (precautions). It is likely that other interactions exist and can be clinically significant in patients not selected such as testing. The development of tools to study the influence of P-GP on the PK and PD of dabigatran is therefore interesting. As the P-GP has a genetic polymorphism, the study of the latter is an important element in the detection of drug interactions. In this sense, clarithromycin, a potent inhibitor of P-GP is a good model to evaluate the primary mechanism of drug interaction of dabigatran and optimize the experimental design of studies to be conducted.

Official title: Investigation Drug-drug Interaction Between Dabigatran and Clarithromycin

Study design: Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Crossover Assignment, Masking: Single Blind (Outcomes Assessor)

Primary outcome: Determination of dabigatran and its metabolites in plasma by LC/MS-MS method

Secondary outcome:

Pharmacodynamic parameters

Genotyping

Minimum age: 18 Years. Maximum age: 35 Years. Gender(s): Male.

Criteria:

Inclusion Criteria:

- affiliated or beneficiary of a social security category

- having signed the inform consent form

- having signed the genetic consent form

- weight between 60 and 85 kg

- normal clinical exam

- normal biological exam

Exclusion Criteria:

- contra-indication to dabigatran

- contra-indication to clarithromycin

- previous history of psychiatric disease, or antidepressant treatment, or convulsion,

or hemorrhagic disease

- smoker

- peptic ulcer

- severe liver disease

- severe kidney failure

- previous surgery within one month

Service de Medecine et Therapeutique, Saint-Etienne 42055, France

Starting date: June 2011
Last updated: March 21, 2012